SNP rs16906252C>T is an expression and methylation quantitative trait locus associated with an increased risk of developing MGMT-methylated colorectal cancer

Methylation of the MGMT promoter is the major cause of O6-methylguanine methyltransferase deficiency in cancer and has been associated with the T variant of the promoter enhancer SNP rs16906252C>T. We sought evidence for an association between the rs16906252C>T genotype and increased risk of developing a subtype of colorectal cancer featuring MGMT methylation, mediated by genotype-dependent epigenetic silencing within normal tissues.By applying a molecular pathologic epidemiology case-control study design, associations between rs16906252C>T and risk for colorectal cancer overall, and colorectal cancer stratified by MGMT methylation status, were estimated using multinomial logistic regression in two independent retrospective series of colorectal cancer cases and controls. The test sample comprised 1,054 colorectal cancer cases and 451 controls from Sydney, Australia. The validation sample comprised 612 colorectal cancer cases and 245 controls from the Australasian Colon Cancer Family Registry (ACCFR). To determine whether rs16906252C>T was linked to a constitutively altered epigenetic state, quantitative allelic expression and methylation analyses were performed in normal tissues.An association between rs16906252C>T and increased risk of developing MGMT-methylated colorectal cancer in the Sydney sample was observed [OR, 3.3; 95% confidence interval (CI), 2.0-5.3; P T represents an expression and methylation quantitative trait locus.We provide evidence that rs16906252C>T is associated with elevated risk for MGMT-methylated colorectal cancer, likely mediated by constitutive epigenetic repression of the T allele. Clin Cancer Res; 22(24); 6266-77. ©2016 AACR

Histone Deacetylase Inhibitor Tributyrin and Vitamin A in Cancer

Bioactive food compounds like vitamin A and the butyrate’s prodrug tributyrin have preventive activities against different types of cancer, and their use in association could represent a promising strategy for cancer treatment and che- moprevention. Both compounds can induce cell differentiation and apoptosis of neoplastic and preneoplastic cells by means of modulation of gene transcription, yet they act through different but interconnected mechanisms. Vitamin A acts through nuclear receptors that are tightly regulated by histone modifications such as acetylation and DNA methylation. Tributyrin modulates transcription of genes by HDACs inhibition and histone hyperacetylation. This chapter describes how epigenetics mediates the antineoplastic and chemopreventive activity of vitamin A, tributyrin, and their derivatives and how their combination can be used to help overcome current limitations in cancer treatment and prevention. We also show how the mechanisms of action of vitamin A and tributyrin have aided in the development of synthetic and bioengineered compounds like synthetic retinoids and structured lipids, respectively.UCR::Vicerrectoría de Docencia::Salud::Facultad de Medicina::Escuela de Medicin